The development of catalytic methods for asymmetric synthesis is one of the foremost achievements in recent chemistry. At present, many broadly useful methods for catalytic asymmetric oxidation and reduction exist; however, far fewer catalytic asymmetric methods for forming carbon-carbon bonds have been devised. This is not only remarkable in view of the importance of carbon-carbon bond formation in synthesis, but also reflects the major difficulties and challenges associated with enantioselective versions of these transformations. The development of asymmetric carbon-carbon bond forming reactions that are new, powerful and practical is of great importance.
Asymmetric conjugate addition reactions with organometallic reagents are one of the most powerful reactions in chemistry. The use of organozincs and Grignard reagents, readily available from alkylhalides, has made asymmetric catalytic carbon-carbon bond formation based on organometallic reagents practical. However, whilst the use of organozincs and Grignard reagents means that obscure reagents are no longer required, these reagents are still far from ideal. Organometallic procedures have been extensively developed, but suffer from a number of significant limitations. For instance, in the synthesis of complex molecules, functional groups may be present which are incompatible with organometallic reagents. Even the use of a protecting group strategy, which blocks incompatible reaction sites, is often ineffective, due to the reactivity of organometallic reagents and the extreme sensitivity of many asymmetric procedures. Moreover, the reactivity of organometallic reagents is associated with serious safety issues. Asymmetric procedures are typically highly sensitive to reaction conditions such that only particular solvents may be used. Asymmetric organometallic addition reactions must be also be performed at cryogenic temperatures (e.g. less than −30° C.) for high levels of selectively to be obtained. This is not usually possible in industry and so represents a serious limitation of these methods. The aforementioned methods are generally too reactive, too expensive and/or of limited availability.
Particular problems are encountered in the enantioselective synthesis of all-carbon quaternary centres. The ability to construct quaternary centres with high levels of enantioselectivity is widely regarded as one of the most important and challenging goals in asymmetric catalysis. Current approaches to this problem involve transition-metal catalysed asymmetric conjugate addition reactions to trisubstituted Michael acceptors. However, once again, such techniques rely on the use of highly reactive pre-made organometallic reagents that can present practical and safety issues. The use of functionalized nucleophiles in these procedures, essential for providing products ready for further elaboration, can also be problematic because of the incompatibility of functional groups with organometallic reagents.
Maksymowicz et al (Nature Chemistry, 2012, 4, 649-654) describe a catalytic asymmetric conjugate addition process in which carbon-carbon bond formation is achieved using alkenes as alkylmetal equivalents. The disclosed process involves the use of a catalytic complex comprising a metal source (e.g. a copper source) and a non-racemic chiral ligand (e.g. a phosphoramidite ligand).
There exists a need in the art for further catalysts for use in processes for the asymmetric synthesis of organic compounds. In particular, there exists a need in the art for improved catalysts for use in such processes.